Activation of innate immunity during development induces unresolved dysbiotic inflammatory gut and shortens lifespan.

Early-life inflammatory response is associated with risks of age-related pathologies. How transient immune signalling activity during animal development influences life-long fitness is not well understood. Using Drosophila as a model, we find that activation of innate immune pathway IMD signalling in the developing larvae increases adult starvation resistance, decreases food intake, and shortens organismal lifespan. Interestingly, lifespan is shortened by the IMD activation in the larval gut and fat body, while starvation resistance and food intake are altered by that in neurons. The adult flies developed with IMD activation show sustained IMD activity in the gut, despite complete tissue renewal during metamorphosis. The larval IMD activation increases an immuno-stimulative bacterial species Gluconobacter sp. in the gut microbiome, and this dysbiosis is persistent to adulthood. Removing gut microbiota by antibiotics in adult mitigates intestinal immune activation and rescues the shortened lifespan. This study demonstrates that early-life immune activation triggers long-term physiological changes as highlighted as an irreversible gut microbiota alteration, prolonged inflammatory intestine, and concomitant shortening of the organismal lifespan.